Trace elements in pancreatic cancer

Abstract Background Pancreatic cancer (PCA) is an extremely aggressive malignant cancer with an increasing incidence and a low five‐year survival rate. The main reason for this high mortality is that most patients are diagnosed with PCA at an advanced stage, missing early treatment options and opportunities. As important nutrients of the human body, trace elements play an important role in maintaining normal physiological functions. Moreover, trace elements are closely related to many diseases, including PCA. Review This review systematically summarizes the latest research progress on selenium, copper, arsenic, and manganese in PCA, elucidates their application in PCA, and provides a new reference for the prevention, diagnosis and treatment of PCA. Conclusion Trace elements such as selenium, copper, arsenic and manganese are playing an important role in the risk, pathogenesis, diagnosis and treatment of PCA. Meanwhile, they have a certain inhibitory effect on PCA, the mechanism mainly includes: promoting ferroptosis, inducing apoptosis, inhibiting metastasis, and inhibiting excessive proliferation.


| INTRODUCTION
Pancreatic cancer (PCA) is an extremely aggressive malignant cancer that is the fourth leading cause of cancer death globally 1 and the sixth leading cause of cancer death in China. 2 The incidence of PCA is increasing annually, and its rank among cancer causes of death is constantly increasing. 3PCA has a high mortality rate, with a 5-year survival rate of no more than 10%, 1 mainly because >80% of patients are already in the advanced stage when they are diagnosed, missing the optimal treatment opportunity. 4Improving the diagnosis and treatment status of PCA is the only way to reduce its incidence, increase its early diagnosis rate and improve its therapeutic efficacy.
Risk factors for PCA include smoking, drinking, obesity, diabetes, chronic pancreatitis, and genetics. 5,6Trace elements are essential nutrients in the human body and play an important role in normal physiological functions.In addition to dietary intake, the concentration of trace elements in the environment (such as soil, water, and air) will also affect the level of trace elements in the human body.When the concentration of trace elements in the environment is high or low, the body will also increase or decrease absorption.Manganese has strong redox activity and plays an important role in biological processes such as energy metabolism, antioxidant activity, detoxification, musculoskeletal growth, and brain and nerve function regulation. 7Zinc is involved in cell differentiation, division, growth, transport, and gene expression 8 and is involved in more than 2000 transcription factors and 300 enzymes. 9Copper is involved in signaling pathways such as active oxygen metabolism, cellular energy metabolism, iron absorption, and signal transduction. 10While maintaining normal physiological functions, trace elements are closely related to certain diseases in the human body.Low levels of selenium in the body may increase the risk of cardiovascular disease, inflammatory bowel disease 11 and pregnancy complications. 12Long-term exposure to manganese can increase the risk of Parkinson's disease, 13 which has been validated in animal experiments. 14The serum selenium concentration in diabetic patients is higher than that in healthy individuals. 15However, serum concentrations of zinc and iron in obese women are lower than those in healthy individuals. 16n addition, trace elements also play important roles in tumors.Serum strontium concentration in breast cancer patients is higher than that in healthy individuals. 17astric cancer tissues contain higher concentrations of iron, magnesium, and arsenic than noncancerous tissues. 18Colorectal cancer tissues have higher concentrations of zinc, chromium, copper, aluminum and lead than noncancerous tissues. 19A controlled study involving 118 patients with PCA and 399 healthy individuals showed that high concentrations of cadmium, arsenic and lead significantly increase the risk of PCA, while high concentrations of selenium and nickel are negatively correlated with the risk of PCA. 20n addition to the risk of tumors, the relevant mechanisms of trace elements in the development and treatment of tumors have also been studied.Arsenic may play a carcinogenic role through the PI3K/AKT/mTOR pathway, EGFR, 21 Ras/Raf/MEK/ERK 22 and Nrf2. 23Copper plays a key role in cancer initiation signaling pathways, such as the MAPK-ERK, 24 P38 MAPK, 25 ULK 26 and PDK1-AKT pathways. 26MnCl2, an agonist of cGAS-STING, promotes the production of type I interferon, 27 manganese molybdate nanoparticles reduce the expression of glutathione in tumors, 28 and MnO 2 promotes the production of reactive oxygen species (ROS), 29 all of which can promote the ferroptosis of tumor cells.Zinc can inhibit tumor growth by negatively regulating NF-κB transcription factor activity and exerting antioxidant effects. 30The antitumor effects of selenium may involve the following mechanisms: downregulating hypoxia-inducing factors, inhibiting tumor angiogenesis, 31 promoting DNA repair, 32 and inhibiting tumor cell proliferation. 33race elements are strongly linked to metabolic diseases such as diabetes and obesity, and they are risk factors for PCA.Differences in trace element levels between PCA patients and healthy individuals have also been reported.These findings all prove that there is a close association between trace elements and PCA (Figure 1).This review summarized the associations between different trace elements and the risk of PCA (Table 1), summarized the anti-pancreatic cancer mechanism involving trace elements, aimed to clarify the application of trace elements in PCA, and provided a new reference for the prevention, diagnosis, and treatment of PCA.
F I G U R E 1 Association between trace element levels and pancreatic cancer incidence.

T A B L E 1
The concentrations of trace elements with PCA.

Index Sample size Results Reference
Selenium Intake Case = 1424 Selenium intake was negatively associated with the risk of PCA (RR = 0.659, 95% CI = 0.489-0.889).
Selenium Intake / Selenium intake was negatively associated with the risk of PCA (OR = 0.47, 95% Cl = 0.26-0.85).PCA with occupational exposure to Ahs had higher concentration of vanadium in their toenails (p < 0.05).
Selenium usually exists in nature in the oxidation states of −2, 0, +4, and + 6.In living organisms, selenium exists in two forms, one as selenium and the other as a component of various compounds (such as selenates, selenites, selenomethionine, selenocysteine, and proteins containing these amino acids).Selenium affects the activation and differentiation of macrophages, NK cells, B cells, and T cells, mainly by stimulating the antibody formation and activity of helper T cells, cytotoxic T cells and NK cells. 34t the same time, the increase of selenium intake will increase the abundance of lactobacillus in the gut. 35The human body contains approximately 14-21 mg of selenium, which is mainly distributed in the liver, pancreas, kidney, spleen, tooth enamel, and nails.Selenium-rich plants are the main source of selenium in the human diet, including selenium-rich rice, selenium-rich wheat, mushrooms, garlic, black sesame, black beans, etc.The recommended intake of selenium for adults is 70-200 μg day −1 , and organic selenium is healthier and safer than inorganic selenium. 36After ingestion, selenium is mainly absorbed in the duodenum and small intestine, reaches the liver through the portal vein, and is subsequently transported to peripheral tissues through the blood circulation with the selenium protein as a carrier.The liver regulates the amount of selenium in the body, and excess selenium is excreted mainly through the urine and feces.Excessive accumulation of selenium in the body is rare and is mainly seen in drinking water with high selenium content, or in certain jobs where there is frequent exposure to selenium.The main manifestations of excessive selenium accumulation are hair loss, nail abnormalities, and dermatitis.The association between selenium and PCA has been extensively studied.A meta-analysis of 1424 patients with PCA 37 and a meta-analysis of 6 studies suggested that higher selenium intake may decrease the risk of PCA 38 ; these results may be related to the use of selenium as a dietary antioxidant. 39,40A retrospective study indicated that reduced serum selenium concentrations were associated with an increased risk of PCA, and high concentrations of selenium in patients with PCA were associated with prolonged survival. 41A controlled study involving 118 patients with PCA and 399 healthy individuals revealed that high concentrations of selenium were negatively correlated with the risk of PCA. 20Taken together, these findings indicate that high concentrations of selenium can decrease the risk of PCA.However, some scholars came to the opposite conclusion.After the concentrations of selenium in the pancreatic juice of patients with PCA, patients with chronic pancreatitis and healthy individuals were measured, it was found that the concentration of selenium in pancreatic juice was strongly correlated with the risk of PCA.Compared with that of healthy individuals, the risk of PCA was 160% greater for every 1 SD increase in the selenium concentration and 480% greater for every 1 SD increase in the sum of the chromium and selenium concentrations. 42Interestingly, the serum selenium concentrations of 303 patients with PCA and 606 healthy individuals were analyzed, and no significant correlation was found between the serum selenium concentration and the risk of PCA. 43These findings led to a contradiction between the previous association between the selenium concentration in the body and the risk of PCA, and additional studies are needed to provide additional evidence.Current studies have indicated that high concentrations of selenium can decrease the risk of PCA, and the underlying mechanism has been extensively explored (Figure 2).Organic selenium can release iron from mitochondria to increase the sensitivity of pancreatic cancer cells (PCACs) to ferroptosis, thus inhibiting tumor growth. 44A new mechanism for the toxicity of novel methylselenoesters on PCACs was proposed: downregulating cell division control protein 42 homolog (CDC42) and its downstream effector β1integrin (CD29) to induce cell segregation, leading to inner cell formation and inner cell death. 45Sodium selenite decreases the expression of genes that promote PCA metastasis (CEMIP, DDR2, PLOD2, and P4HA1) and increases the expression of the ATF3 gene, which promotes ferroptosis in PCACs, thereby specifically reducing the activity of PCACs and inhibiting tumor growth. 46NF-κB is involved in the development of PCA and inhibits the apoptosis of PCACs. 47A novel selenoaspirinyl compound that can induce caspase-mediated apoptosis and G1 cell cycle arrest inhibits NF-κB signaling to inhibit PCACs proliferation, and it can enhance the cytotoxicity of gemcitabine to PCA. 48As photosensitizing agents for photodynamic therapy, CdSe/ZnS quantum dots increase ROS production in PCACs, upregulate Bax, and caspase-3 and downregulate Bcl-2 to induce apoptosis in PCACs, thus inhibiting the proliferation of PCA. 49In summary, the anti-pancreatic cancer mechanisms associated with selenium mainly include promoting apoptosis, promoting ferroptosis, inhibiting metastasis, and inhibiting excessive proliferation.
In addition, selenium has also shown great application value in the treatment of PCA.A study showed that the combination of selenium and gemcitabine has a synergistic anticancer effect on BxPC-3 cells, 50 and selenium enhances the anticancer activity of gemcitabine.Selenium participated in the formation of a carrier named Abraxane@MoSe, which can accurately guide local photothermal chemotherapy in vivo, reduce cancer-related fibroblasts, and enhance the synergistic treatment efficacy of PCA. 51A biocompatible near-infrared fluorescence probe called glucose-functionalized Ag2Se QDs, which can target the imaging of PCA, 52 is highly valuable for the diagnosis and accurate treatment of PCA.A study of 271 patients (including PCA) revealed that selenium deficiency was common in PCA patients and that selenium supplementation improved overall quality of life, physical and emotional functions, and fatigue. 53Therefore, selenium supplementation may improve the prognosis of PCA patients.

| COPPER
Copper is present in the human body mainly as ceruloplasmin, which plays an important role in electron transport and redox reactions.It can cause the pro-activation state of Th1 and Th2 lymphocytes 54 and promote the proinflammatory state of macrophages. 55In addition, high levels of copper intake promote the development of antimicrobial resistance in the gut microbiota. 56The adult body contains approximately 0.1 g of copper, 50%-70% of which is present in muscle and bone, 20% in the liver, and 5%-10% in the blood; moreover, the amount of copper distributed in the pancreas is lower.Dietary copper is the main source of copper in the human body, including beef liver, oysters, mushrooms, cashews, sunflower seeds, potatoes, etc.After oral intake, copper-containing food is mainly absorbed in the duodenum, reaches the liver for metabolism through the portal vein system, and then is distributed throughout the whole body through the blood circulation.
Copper-transporting ATPases maintains intracellular copper levels, and its inactivation leads to intracellular copper accumulation and excretion disorders.Copper is excreted into the body mainly through bile in the intestine and is subsequently excreted in the form of feces.
High concentrations of copper may increase the risk of PCA.A comparison of the serum copper concentrations between 100 patients with PCA and 100 healthy individuals showed that patients with PCA had higher serum copper concentrations. 41A study involving urine samples from 67 individuals showed that patients with PCA had higher concentrations of copper in their urine. 57Similarly, the mechanism of action of copper in treating pancreatic cancer has also been extensively studied (Figure 3).Exogenous copper can bind to glutathione peroxidase 4 (GPX4) cysteines C107 and C148 to increase GPX4 ubiquitination and the formation of GPX4 aggregates, subsequently enabling GPX4 autophagy to enhance ferroptosis in PCACs, 58 thus playing a role in PCACs.[CuII2I23]3 also exhibited anti-pancreatic cancer (APCA) activity by activating the MAPK pathway to promote ferroptosis. 59 study noted that copper-tolfenamic acid could inhibit the growth of PCACs and that the expression of TP53 and DDIT3 increased, while the expression of Sp1, ErbB2, and STAT3 decreased.60 TP53 is a common tumor suppressor gene that can promote the apoptosis of cancer cells.61 Like TP53, DDIT3 can also promote the apoptosis of cancer cells.62 Sp1 inhibits apoptosis.63 ErbB2 is a common oncogene 64 that can activate AKT/STAT3 to promote the F I G U R E 2 Mechanism of selenium in anti-pancreatic cancer.Selenium is involved in APCA through inducing apoptosis, promoting ferroptosis, inhibiting metastasis, and inhibiting excessive proliferation.ATF3, activating transcription Factor 3; Bax, Bcl2associated x; Caspase, cysteinyl aspartate specific proteinase; CD29, β1integrin; CDC24, cell division control protein 42 homolog; CEMIP, cell migration inducing hyaluronic binding protein; DDR2, discoidin domain receptor 2; NF-κB, nuclear factor κB; P4HA1, prolyl 4-hydroxylase alpha polypeptide 1; PLOD2, procollagen-lysine,2-oxoglutarate 5-dioxygenase 2; ROS, reactive oxygen species.
occurrence and metastasis of PCA. 65The heteroleptic Cu(II)-phenanthroline-UDCA upregulates the chaperone BiP, the proapoptotic protein CHOP, and the transcription factor ATF6 to promote apoptosis. 66The Cu(II)-cyamonin complex can produce ROS to induce apoptosis, inhibit the AKT signaling pathway and downregulate c-Myc to inhibit the growth of PCACs and metastasis. 67As mentioned above, the AKT signaling pathway promotes the metastasis of PCA, while the main carcinogenic mechanism of c-Myc is to promote cell proliferation. 68Cu(I) and Cu(II) complexes based on lonidamine-conjugated ligands can also induce PCACs death through apoptosis. 69Zinc-doped copper oxide nanocomposites induced autophagy in PCACs by activating the AMPK/mTOR pathway, 70 which led to the death of PCACs.Roy J et al. noted that cu can enhance the cytotoxicity of quinolyl pyrazinamides to PCACs, 71 but the specific mechanism involved remains to be studied.Polypyridyl-based copper phenanthrene complexes can specifically recognize guanine-cytosine (G-C)-enriched sequences and cause cytotoxicity in PCA. 72Copper(ii)l/dvaline-(1,10-phen) complexes effectively target telomere G-quadruplexes and undergo oxidative cleavage, demonstrating cytotoxicity to PCA. 73 Copper promotes APCA activity mainly through promoting apoptosis, promoting ferroptosis, inhibiting metastasis, promoting autophagy, and targeting tumor DNA damage.
Copper also has great potential in the diagnosis and orientation of PCA.Injection of copper-64-labeled drugs can improve the sensitivity of PET-CT for diagnosing PCA and can detect tumors with a minimum diameter of 3 mm. 74This achievement can be said of a large step forward in the early detection of PCA.Copper-doped nanomaterials can also be used as drug carriers to enhance the killing effect of drugs on PCA through specific targeted drug delivery 73,[75][76][77] and improved drug tumor penetration. 78Interestingly, copper chelating agents could silence CTR1 and downregulate the phosphorylation of AKT/ mTOR molecules after reducing copper concentrations, thus inhibiting PCA progression and improving the anticancer effect of rapamycin on PCA. 79,80These findings further confirmed that copper homeostasis can be used as an emerging target for treatment of PCA.Copper plays an important role in the discovery, diagnosis and treatment of PCA, but different concentrations of copper have different effects on PCA, and maintaining copper homeostasis is crucial for ensuring the health of the pancreas.Arsenic has been identified as a carcinogen by the International Agency for Research on Cancer and has a definite carcinogenic effect on the human body.Arsenic is also an immunotoxicant that promotes the antiinflammatory phenotype of macrophages, inhibits T cell proliferation, B cell proliferation, and antibody production. 81Moreover, long-term exposure to arsenic can also reduce the abundance of Clostridiaceae, Rikenellaceae, and Parabacteroides in the gut. 82Arsenic exists in nature mainly in the form of inorganic arsenic and is widely distributed in soil, water, and air.Arsenic is absorbed by the body through exposure to an environment contaminated with arsenic, mainly through inhalation or oral absorption.Drinking water containing arsenic is the most common form of arsenic.When absorbed by the body, arsenic binds to erythrocytes and is deposited in the liver, kidneys, muscles, bones, hair, skin, and nails through the blood circulation, where it can cause toxicity.While arsenic is harmful to the kidneys, it is also excreted in the urine.
Several studies have pointed to a strong association between the concentrations of arsenic in the body and the risk of PCA.The concentrations of trace elements in the toenails of 118 patients with PCA and 399 healthy individuals were analyzed, and it was found that high concentrations of arsenic can increase the risk of PCA. 20A study involving 78 patients with PCA and 416 healthy individuals indicated that patients with PCA had higher concentrations of arsenic in their toenails, but the difference was not statistically significant. 83A cohort study of 11,405 patients with PCA indicated that long-term drinking of water contaminated with arsenic increased the risk of PCA. 84nterestingly, the poison arsenic has shown strong potential in the treatment of PCA, and its mechanism involves mainly promoting apoptosis, inhibiting metastasis, and inhibiting excessive proliferation (Figure 4).Arsenic promoted the apoptosis of PCACs cells by downregulating BCL-2. 85A study showed that both arsenic trioxide (ATO) and pyrrolidine dithiocarbamate-arsenic trioxide (PDTC-ATO) can promote apoptosis to inhibit PCACs, and the inhibitory effect of PDTC-ATO is stronger than that of ATO 86 ; moreover, both can downregulate Pirh2.Pirh2 can downregulate the expression of P53, 87 thereby inhibiting apoptosis and causing adverse effects. 61The BET bromodomain inhibitor JQ1, 88 heme oxygenase-1, 89 hypoxia-inducing factor-1 inhibitor 90 and docosahexaenoic acid 91 can all synergistically enhance ATO-induced apoptosis in PCACs.
In addition to inhibiting the proliferation of PCACs, ATO can also enhance the sensitivity of PCACs to gemcitabine by downregulating TIMP1/PI3K/AKT/mTOR signaling, 92 inhibiting the activation of pancreatic stellate cells, 93 and inhibiting the expression of Skp2. 94TIMP1/PI3K/AKT/ mTOR has an inhibitory effect on apoptosis, 92 while Kp2 has a carcinogenic effect by activating Myc and causing cell proliferation. 95ATO, while increasing the sensitivity to chemical drugs, can also play an APCA role through multiple mechanisms.In addition to gemcitabine, ATO can also overcome the resistance of PCACs to erlotinib, 96 thereby enhancing the effect of erlotinib on APCA.ATO also functions as a sensitizer in radiotherapy for PCA, 97 and its mechanism may involve reversing the hypoxic environment and downregulating CD24 and CD44.Coincidentally, CD24 and CD44 have been identified as being characteristically expressed in PCA stem cells. 98ATO plays an important role both in direct APCA and in improving therapeutic efficacy, and it has great prospects in the treatment of PCA.In addition to ATO, arsenic sulfide also promoted APCA activity, which may be achieved by activating caspase-3 and caspase-9 to induce apoptosis. 99Sodium meta-arsenite inhibited metastasis by inhibiting NF-κB to promote apoptosis and inhibit VEGF-C activity, 100 and it can enhance the anticancer activity of gemcitabine against PCA by downregulating EGFR and MMP2. 101EGFR 102 and MMP2 103 both play important roles in promoting the growth and metastasis of PCACs.Oxidative phosphorylation inhibitors can inhibit the recurrence of KRAS-mutant PCA, 104 and ATO, an oxidative phosphorylation inhibitor, 105 may inhibit the recurrence of PCA.Arsenic has shown strong APCA effects, but considering its own toxic effects, its safety in practical applications remains to be studied.

| MANGANESE
Manganese is usually found in the natural positive oxidation state (+2, +3, +4, +6, and + 7); the most common oxidation states in living organisms are +2 and + 3, which are involved in the composition of a variety of coenzymes in the body and play key roles in protecting cells from damage by the superoxide free radical O2−.Moreover, manganese can also act as an immune enhancer, stimulating humoral and cellular immune responses, inducing antibody production and CD4/CD8T cell proliferation and activation. 106Manganese exposure also has an effect on microbiota, it can significantly reduce Bacteroides in the gut of male mice. 107Interestingly, there is a high content of Bacteroidetes in human PCA tissues, which may promote the development of PCA by inducing immunosuppression. 108But, whether manganese inhibits PCA by reducing the abundance of Bacteroidetes needs further study.
In the human body, manganese comes from food intake (such as nuts, whole grains, and legumes), inhalation, and skin penetration; is rapidly absorbed in the gastrointestinal tract and lungs; and is subsequently distributed through the blood circulation to soft tissues (~60%), liver (30%), pancreas (5%), kidney (5%), bone (0.5%), and brain (0.1%).Excess manganese is mainly combined with bile in the liver and subsequently excreted in the feces. 109everal studies have shown the close association between manganese and PCA.A study involving 114 patients with PCA showed that the concentration of manganese in the toenails of patients with PCA who were occupationally exposed to aromatic solvents (Ahs) was significantly greater than that of patients who were not exposed to Ahs, 110 suggesting that manganese combined with Ahs may increase the risk of PCA.A controlled study involving 78 patients with PCA and 416 healthy individuals showed the opposite conclusion: a lower concentration of manganese in toenails was associated with a greater risk of KRAS-mutant PCA. 83Individuals are prone to diabetes when they have both low and high manganese concentrations, and there is a U-shaped correlation between diabetes and manganese concentrations in the body. 111Diabetes is a high-risk factor for PCA. 5 These findings suggest that manganese homeostasis is essential for maintaining a healthy state in the pancreas.At present, additional research on the mechanism underlying the interaction between manganese and PCA has focused on APCA (Figure 5).In cell F I G U R E 5 Mechanism of manganese in anti-pancreatic cancer.Manganese is involved in APCA through mainly promoting ferroptosis and inhibiting excessive proliferation.JAK2/STAT3, Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway; MAPK, mitogen-activated protein kinase signaling pathway; ROS, reactive oxygen species.
experiments, researchers used manganese-doped zinc selenide quantum dots for gene delivery and found that they could induce sequence-specific silencing of carcinogenic Kras mutations in PCA, 112 thus inhibiting the occurrence of PCA.Manganese-based Prussian blue nanoparticles induced ferroptosis of PCA through the MAPK pathway, 113 while PH-sensitive PtMn nanoparticles could specifically recognize PCACs and increase the production of intracellular ROS to enhance ferroptosis, 114 thus inhibiting the proliferation and metastasis of PCA.These results indicate that nanoparticles composed of manganese can promote ferroptosis in various ways and exhibit the APCA effect.Manganese superoxide dismutase (MnSOD) had a low expression in PCA, 115 in other words, high expression of MnSOD can inhibit the occurrence and development of PCA, and it is coincidental that both metformin 116 and pterostilbene 117 can increase the expression and activity of MnSOD to inhibit PCA.Liu F et al. introduced galangin into a Fenton-like catalyst (SiO2@MnO2) to form hybrid nanomedical drugs in response to TME stimulation and confirmed in vivo and in vitro that the nanomedical drug can stimulate intracellular ROS concentrations and inhibit the JAK2/STAT3 cell proliferation pathway to exert APCA effects. 118The present study showed that manganese plays an APCA role mainly by inducing ferroptosis and inhibiting the cell proliferation pathway, and additional studies are needed to uncover the APCA mechanism of manganese.
Manganese also plays an important role in the treatment of PCA.Although manganoporphyrins can enhance the toxic effect of gemcitabine on PCA, 119 they can also enhance the inhibitory effect of ascorbate on PCA. 120nO 2 can promote the multisource production of ROS and enhance the effectiveness of photodynamic therapy and photothermal therapy. 121The manganese complex plays a role as a radiosensitizer 122 and can also enhance the effect of radiotherapy by dual targeting mechanisms, namely, ameliorating hypoxia and inhibiting angiogenesis. 123Avasopasem manganese can increase the concentration of hydrogen peroxide in PCACs, reduce damage to normal cells during radiotherapy, and promote stereotactic radiotherapy of tumors. 124Moreover, manganese porphyrin can produce powerful ROS under ultrasonic exposure to enhance the efficacy of sonodynamic therapy for PCA. 125At present, manganese has shown potential therapeutic effects in chemical, radiotherapy, photodynamic therapy, photothermal therapy and acoustodynamic therapy, and manganese is of great value in the treatment of PCA.

| OTHER TRACE ELEMENTS
In addition to the above elements, other related elements have also been studied (Figure 6).A study involving 78 patients with PCA and 416 healthy individuals indicated that patients with KRAS wild-type PCA had higher concentrations of iron in their toenails than did those with KRAS mutant PCA. 83A controlled study involving 114 patients with PCA noted that patients with PCA occupationally exposed to Ahs had higher concentrations of iron in their toenails, but the difference was not statistically significant. 110Thus, the association between iron and the risk of PCA is not clear.Ferroptosis is a form of cell death in PCA that is caused by oxidative damage induced by excessive iron. 126In addition, iron oxide nanoparticles have been used to treat PCA through various methods, including photothermal therapy, immunotherapy 127 and chemotherapy. 128Superparamagnetic iron oxide nanoparticles can be targeted to identify PCACs, enhance magnetic resonance imaging of PCA, 129 and inhibit MUC4-mediated metastasis in PCA, 130 thus playing a role in the treatment of PCA.However, an animal study suggested that a high-iron diet first promoted the release of 8-hydroxy-2′-deoxyguanosine, activated the STING pathway, and ultimately led to macrophage infiltration and activation of KRAS-driven PCA. 131Another study also noted that excessive iron decreases the expression of inhibitory P53 and leads to the occurrence of PCA. 132Iron is also a double-edged sword for PCA, and maintaining iron homeostasis in the body is crucial to the health of the pancreas.A meta-analysis involving six studies showed that high concentrations of zinc were significantly associated with a reduced risk of PCA. 133yndecan binding protein (SDCBP) can promote tumor proliferation and metastasis. 134An animal study revealed that zinc pyrithione can inhibit the progression of PCA by inhibiting SDCBP. 135Like arsenic, cadmium is also a recognized human carcinogen. 136Several studies have reported that cadmium exposure increases the risk of PCA. 20,83,137Moreover, mechanistic studies have indicated that cadmium may cause PCA by altering mitochondrial function 138,139 and upregulating miR-221, 140 among which miR-221 is one of the most carcinogenic miRNAs in PCA. 141However, a study noted that longterm exposure to cadmium had no significant effect on the survival of patients with PCA. 142Lead is classified as a 2A carcinogen by the International Agency for Research on Cancer and has been associated with gastric, brain, kidney, lung, 143 and PCA. 20However, the carcinogenic mechanism of lead in PCA has not been further studied.It has been reported that a high concentration of nickel is negatively correlated with the risk of PCA. 20,83Nickel can change the expression concentrations of miRNAs, and miRNAs play important roles in the occurrence and progression of PCA. 144Nickel nanowires may be effective apoptotic agents for PCA treatment, and this effect is mediated by ROS. 145Chromium has been shown to increase the risk of PCA, 42 but additional evidence is needed to support this finding.The organotin complex is cytotoxic to PCA, 146 but its specific mechanism remains to be further studied.HIF-1α counteracts the aggressiveness of PCA induced by hyperglycemia, and the concentration of HIF-1α is positively correlated with the concentration of CoCl 2 , which may reduce the aggressiveness of PCA by increasing the expression of HIF-1α. 147A study noted that CoCl 2 can effectively induce apoptosis in PCACs by upregulating HIF-1α. 148CoCl 2 can construct an anoxic environment for PCACs, 149 and hypoxia can activate HIF-1α. 150CoCl 2 may increase the expression of HIF-1α by creating an anoxic environment, thus inhibiting PCA.Several studies have shown that molybdenum can damage pancreatic β cells and lead to diabetes, 139,151 while diabetic patients have a greater risk of PCA 152 ; moreover, the association between molybdenum and PCA is worth studying.Higher concentrations of vanadium are associated with an increased risk of PCA. 38Interestingly, a number of studies have indicated that the vanadium complex has APCA activity, mainly through promoting apoptosis 153,154 and cell cycle arrest. 155,156A cohort study in 2007 indicated that long-term exposure to aluminum increased the risk of PCA, 157 but the link between aluminum and PCA has yet to be determined.

| CONCLUSION
During the development of PCA, selenium, manganese, and iron had dual effects on PCA, and they both promoted and inhibited the development of PCA.Maintaining homeostasis is very important for the health of the pancreas.Selenium, copper, and iron have shown unique value in the diagnosis of PCA by targeting imaging and improving diagnostic sensitivity.In vivo and in vitro experiments have verified that a variety of trace elements or their participating compounds have APCA activity, and the underlying mechanisms include promoting ferroptosis, inducing apoptosis, inhibiting metastasis, and inhibiting excessive proliferation.Selenium and manganese also have a certain impact on the prognosis of patients with PCA and can be used to construct prognostic models, even improving the prognosis of patients with PCA.However, most of the current literature reports are limited to only the research level, and there is still a lack of practical clinical application.However, additional studies are needed to verify the effectiveness and safety of these agents in clinical application.Therefore, evaluating the efficacy and safety of trace element therapy for the prevention, diagnosis and treatment of PCA is an important direction worth studying in the future.

F I G U R E 6
Mechanism of other trace elements in anti-pancreatic cancer.This figure describes the APCA mechanisms associated with other trace elements, including inducing apoptosis, promoting ferroptosis, inhibiting metastasis, and inhibiting excessive proliferation.HIF-1α, hypoxia-inducible factor-1α; MUC4, transmembrane glycoprotein; DCBP, syndecan binding protein.